Ginseng is a top-selling herbal supplement that is purported to increase vitality and improve health and, consequently, is used as a complementary therapy by cancer patients. There are some reports that ginseng use may be associated with increased survival and quality of life in breast cancer patients. In our preliminary data, we demonstrate that ginseng increases the anti-cancer efficacy of the chemotherapeutic doxorubicin on breast cancer cells in vitro and on tumor growth in vivo, and further prevents the weight loss associated with doxorubicin treatment. Ginseng contains over 30 different ginsenosides and polysaccharide components and these are considered the major bioactive constituents in the ginseng root. We provide preliminary evidence that ginseng polysaccharides stimulate the innate immune system and induce macrophages to produce increased cytokine release. In turn, the ginsenosides may act directly to inhibit cancer cell proliferation. Our preliminary studies using cultured human breast cancer MCF-7 cells show that together the cytokines and ginsenosides may be responsible for the ability of ginseng to exert anti-cancer effects. What remains is to test these findings in an in vivo model and determine how ginseng's constituents contribute to the complementary effectiveness of ginseng during doxorubicin treatment. First, female nude mice will be inoculated with human breast cancer MCF-7 cells and the effects of supplemental ginseng on the ability of doxorubicin to prevent tumor growth and induce systemic toxicity will be measured. We will utilize two treatment paradigms that are designed to simulate the individual who starts taking ginseng as soon as the breast cancer is diagnosed (pre-chemotherapy), or the individual who starts taking ginseng when chemotherapy is initiated. At the end of the study, tumor tissues will be analyzed for proliferation and apoptotic indices, blood for activation of innate immune responses and systemic toxicity, and heart tissue will be analyzed for cardiotoxicity associated with doxorubicin treatment. Lastly, human mammary epithelial and breast cancer cell lines will be treated with ginsenosides and/or cytokines to determine the signaling and apoptotic pathways that may be responsible for ginseng-induced sensitization to doxorubicin therapy. We hypothesize that the bioactive ginseng constituents will act in concert through different mechanisms of action to maximize the safety and complementary effectiveness of ginseng. These data will provide the first translational step towards providing evidence-based information to heath care professionals and the public regarding the use of ginseng and its constituent-enriched extracts in complementary breast cancer therapy. . PUBLIC HEALTH RELEVANCE: This R21 grant project will determine how ginseng's ginsenoside and ginseng polysaccharide constituents contribute to the complementary effectiveness of ginseng during doxorubicin treatment for breast cancer in a nude mouse model;and, secondly, address the mechanisms of action of ginseng's constituents. It is our hypothesis that these bioactive ginseng constituents act together through different mechanisms of action to maximize the safety and complementary effectiveness of ginseng. These data will provide the first translational step towards providing evidence-based information to heath care professionals and the public regarding the use of ginseng and its constituent-enriched extracts in complementary breast cancer therapy.